Comparative healing response after sirolimus- and paclitaxel-eluting stent implantation in a pig model of restenosis.

OBJECTIVE: We compared local vessel healing and inflammatory responses associated with nonoverlapping sirolimus-eluting stents (SES) and paclitaxel-eluting stents (PES). BACKGROUND: Sirolimus and paclitaxel may have different effects on vascular healing. In the present study, we analyzed the local histologic effects of drug-eluting stents (DES). METHODS: We placed 43 stents (22 PES and 21 SES) in 16 Yucatan minipigs. Stents were randomly assigned and placed in the left anterior descending, circumflex, or right coronary arteries (one stent per artery), covering a region previously injured by balloon angioplasty. RESULTS: Histopathologic analysis showed that the distribution of injury scores was similar between the two stent groups, reflecting the homogeneity of coronary injury secondary to balloon overstretch. Electron microscopy showed complete endothelialization in most cases. Incomplete endothelialization was present in 12.5% of PES and almost 20% of SES at 30 days. In the PES group, moderate to severe inflammation was found in eight arteries, whereas only one vessel had moderate inflammation in the SES group. Severe inflammation was observed significantly more often in the PES than in the sirolimus group (P = 0.006). With the PES group, stent struts overlying side branches had a significantly higher frequency of poor endothelialization scores than did stent struts that did not overlay side branches (P = 0.006). CONCLUSIONS: In this preclinical study in a pig model of in-stent restenosis, implantation of nonoverlapping DES was associated with local inflammatory reactions and decreased endothelial repair. Impaired endothelialization was visualized in the struts overlying side branches.

A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization.

BACKGROUND: The need for repeated treatment of restenosis of a treated vessel remains the main limitation of percutaneous coronary revascularization. Because sirolimus (rapamycin) inhibits the proliferation of lymphocytes and smooth-muscle cells, we compared a sirolimus-eluting stent with a standard uncoated stent in patients with angina pectoris. METHODS: We performed a randomized, double-blind trial to compare the two types of stents for revascularization of single, primary lesions in native coronary arteries. The trial included 238 patients at 19 medical centers. The primary end point was in-stent late luminal loss (the difference between the minimal luminal diameter immediately after the procedure and the diameter at six months). Secondary end points included the percentage of in-stent stenosis of the luminal diameter and the rate of restenosis (luminal narrowing of 50 percent or more). We also analyzed a composite clinical end point consisting of death, myocardial infarction, and percutaneous or surgical revascularization at 1, 6, and 12 months. RESULTS: At six months, the degree of neointimal proliferation, manifested as the mean (+/-SD) late luminal loss, was significantly lower in the sirolimus-stent group (-0.01+/-0.33 mm) than in the standard-stent group (0.80+/-0.53 mm, P<0.001). None of the patients in the sirolimus-stent group, as compared with 26.6 percent of those in the standard-stent group, had restenosis of 50 percent or more of the luminal diameter (P<0.001). There were no episodes of stent thrombosis. During a follow-up period of up to one year, the overall rate of major cardiac events was 5.8 percent in the sirolimus-stent group and 28.8 percent in the standard-stent group (P<0.001). The difference was due entirely to a higher rate of revascularization of the target vessel in the standard-stent group. CONCLUSIONS: As compared with a standard coronary stent, a sirolimus-eluting stent shows considerable promise for the prevention of neointimal proliferation, restenosis, and associated clinical events.

Four-year angiographic and intravascular ultrasound follow-up of patients treated with sirolimus-eluting stents.

BACKGROUND: Despite the proven superiority of sirolimus-eluting stents (SESs) compared with bare stents in the first year after implantation, long-term outcomes of patients treated with these novel devices remain unknown. Our goal was to evaluate the clinical, angiographic, and intravascular ultrasound (IVUS) outcomes of patients treated with SESs 4 years after implantation. METHODS AND RESULTS: The study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR; n=15] and fast release [FR; n=15]). Twenty-six patients underwent 4-year angiographic and IVUS follow-up and had matched assessments at all time points (index and 4-, 12-, 24-, and 48-month follow-up). One death occurred during the study period in a patient with a patent SES. There were no target-vessel revascularizations or thromboses between 2- and 4-year follow-up examinations. There was no stent thrombosis, target-lesion revascularization, death, or myocardial infarction in the SR group up to 4 years. Cumulative event-free survival rate was 87% for the total population (80% in the FR group and 93% in the SR group). In-stent late loss was slightly greater in the FR group (0.41+/-0.49 mm) than the SR group (0.09+/-0.23) after 4 years. One patient in the FR group had a 52% in-stent restenosis lesion. Percent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 4 years (FR=9.1% and SR=5.7%). CONCLUSIONS: This study confirms the longevity of the optimal outcomes observed in patients treated with sirolimus-eluting Bx Velocity stents 4 years after implantation. In-stent lumen dimensions remained essentially unchanged at 4-year follow-up, particularly in the population treated with the currently available SES (SR formulation).

Effects of drug combinations on smooth muscle cell proliferation: an isobolographic analysis.

Although sirolimus is a potent inhibitor of vascular smooth muscle cell (VSMC) proliferation and is effective at preventing restenosis in the majority of clinical revascularization procedures employing sirolimus-eluting stents, some VSMC may escape the antiproliferative effects of sirolimus. The present study examines the effects of combining sirolimus with other known cell cycle-specific antiproliferative agents (cladribine, topotecan or etoposide) on cultured coronary artery VSMC proliferation and utilizes a novel isobolographic approach to determine whether sirolimus/antiproliferative agent combinations produce subadditive, additive or supraadditive potentiation of antiproliferative activity. All agents were found to inhibit coronary artery VSMC proliferation in a dose-dependent manner. Cladribine was found to potentiate the antiproliferative activity of sirolimus in either an additive or supraadditive manner, depending upon the cladribine concentration. Topotecan potentiated the sirolimus antiproliferative activity by simple additivity while etoposide yielded subadditive potentiation. The present results demonstrate the utility of isobolographic analysis for identifying and optimizing antiproliferative drug combinations.

Two-year angiographic and intravascular ultrasound follow-up after implantation of sirolimus-eluting stents in human coronary arteries.

BACKGROUND: The safety and efficacy of sirolimus-eluting stenting have been demonstrated, but the outcome of patients treated with this novel technology beyond the first year remains unknown. We sought to evaluate the angiographic, intravascular ultrasound (IVUS), and clinical outcomes of patients treated with sirolimus-eluting stents 2 years after implantation. METHODS AND RESULTS: This study included 30 patients treated with sirolimus-eluting Bx Velocity stenting (slow release [SR], n=15, and fast release [FR], n=15) in São Paulo, Brazil. Twenty-eight patients underwent 2-year angiographic and IVUS follow-up. No deaths occurred during the study period. In-stent late loss was slightly greater in the FR group (0.28+/-0.4 mm) than in the SR group (-0.09+/-0.23 mm, P=0.007). No patient had in-stent restenosis. At 2-year follow-up, only 1 patient (FR group) had a 52% diameter stenosis within the lesion segment, which required repeat revascularization. The target-vessel revascularization rate for the entire cohort was 10% (3/30) at 2 years. All other patients had < or =35% diameter stenosis. Angiographic lumen loss at the stent edges was also minimal (in-lesion late loss was 0.33+/-0.42 mm [FR] and 0.13+/-0.29 mm [SR]). In-stent neointimal hyperplasia volume, as detected by IVUS, remained minimal after 2 years (FR= 9.90+/-9 mm3 and SR=10.35+/-9.3 mm3). CONCLUSIONS: This study demonstrates the safety and efficacy of sirolimus-eluting Bx Velocity stents 2 years after implantation in humans. In-stent lumen dimensions remained essentially unchanged at 2-year follow-up in the 2 groups, although angiographic lumen loss was slightly higher in the FR group. Restenosis "catch-up" was not found in our patient population.

Sirolimus-eluting stent for the treatment of in-stent restenosis: a quantitative coronary angiography and three-dimensional intravascular ultrasound study.

BACKGROUND: We have previously reported the safety and effectiveness of sirolimus-eluting stents for the treatment of de novo coronary lesions. The present investigation explored the potential of this technology to treat in-stent restenosis. METHODS AND RESULTS: Twenty-five patients with in-stent restenosis were successfully treated with the implantation of 1 or 2 sirolimus-eluting Bx VELOCITY stents in São Paulo, Brazil. Nine patients received 2 stents (1.4 stents per lesion). Angiographic and volumetric intravascular ultrasound (IVUS) images were obtained after the procedure and at 4 and 12 months. All vessels were patent at the time of 12-month angiography. Angiographic late loss averaged 0.07+/-0.2 mm in-stent and -0.05+/-0.3 mm in-lesion at 4 months, and 0.36+/-0.46 mm in-stent and 0.16+/-0.42 mm in-lesion after 12 months. No patient had in-stent or stent margin restenosis at 4 months, and only one patient developed in-stent restenosis at 1-year follow-up. Intimal hyperplasia by 3-dimensional IVUS was 0.92+/-1.9 mm(3) at 4 months and 2.55+/-4.9 mm(3) after 1 year. Percent volume obstruction was 0.81+/-1.7% and 1.76+/-3.4% at the 4- and 12-month follow-up, respectively. There was no evidence of stent malapposition either acutely or in the follow-up IVUS images, and there were no deaths, stent thromboses, or repeat revascularizations. CONCLUSION: This study demonstrates the safety and the potential utility of sirolimus-eluting Bx VELOCITY stents for the treatment of in-stent restenosis.

Drug-eluting stents: sirolimus and paclitaxel differentially affect cultured cells and injured arteries.

Sirolimus and paclitaxel eluted from stents inhibit cell proliferation and other cellular processes by dramatically different mechanisms. In this study, the effects of sirolimus and paclitaxel on cultured human coronary artery smooth muscle and endothelial cell function or cell cycle changes in balloon-injured arteries were directly compared. Both sirolimus and paclitaxel inhibited smooth muscle and endothelial cell proliferation. However, only paclitaxel inhibited smooth muscle and endothelial cell migration at low (nM) concentrations. Sirolimus arrested smooth muscle and endothelial cells in the G0/G1 phase of the cell cycle without inducing apoptosis while paclitaxel produced apoptosis in both cell types at low nanomolar concentrations. Although both agents blocked neointimal formation, sirolimus applied locally to injured rat carotid arteries increased the percentage of cycling vascular cells in G0/G1 without inducing apoptosis while paclitaxel increased the percentage of cycling cells in S and G2/M phases while inducing apoptosis. These results suggest that sirolimus reduces neointimal hyperplasia through a cytostatic mechanism while paclitaxel produces apoptotic cell death.

Long-term effects of polymer-based, slow-release, sirolimus-eluting stents in a porcine coronary model.

BACKGROUND: Stent-based delivery of sirolimus (SRL) has shown reduction in neointimal hyperplasia and restenosis. The purpose of this study was to evaluate the chronic vascular response and the expression of cell cycle regulators after SRL-eluting stent implantation in a porcine coronary model. METHODS: Forty-nine pigs underwent placement of 109 oversized stents (control, n=54, SRL (140 microg/cm(2)), n=55) in the coronary arteries with histologic analysis and Western blot (PCNA, p27(kip1), CD45, MCP-1, IL-2, IL-6, TNF-beta) at 3, 30, 90 or 180 days. RESULTS: At 3 days, the mean thrombus area was similar for control (0.38+/-0.19 mm(2)) and SRL (0.29+/-0.09 mm(2)) stents. After 30 days, the mean neointimal area was significantly less for the SRL (1.40+/-0.35 mm(2)) versus the control stents (2.94+/-1.28 mm(2), p<0.001). At 90 and 180 days, the mean neointimal area was similar for the SRL (3.03+/-0.92 and 3.34+/-0.99 mm(2)) as compared with control stents (3.45+/-1.09 and 3.65+/-1.23 mm(2)). Western blot analysis demonstrated an increased expression of p27(kip1) in the vessel wall at 90 days for the SRL versus control stents (p=0.05) but with increased levels of PCNA in the SRL as compared with control stents (p=0.003). CONCLUSION: SRL-eluting stents favorably modulate neointimal formation for 30 days in the porcine coronary model. Long-term inhibition of neointimal hyperplasia is not sustained presumably due to delayed cellular proliferation despite increased levels of the cyclin-dependent kinase p27(kip1) in the vessel wall.

Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration.

OBJECTIVES: In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND: Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. METHODS: Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 µg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS: In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). CONCLUSIONS: During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion.

Update on sirolimus drug-eluting stents.

Percutaneous transluminal coronary angioplasty (PTCA) has become the main method of coronary revascularization. However, despite technical advancement, restenosis with incidence rate of 30 to 50% remains a major limitation to the long-term success of PTCA. The introduction of stents has significantly improved capability of interventional cardiology in treatment and prevention of restenosis. Recent experimental studies in animals, clinical studies in humans and multi-center randomized clinical trials with Sirolimus-eluting stents, have demonstrated a significant reduction in vasculoproliferative response with no intimal tissue growth. Moreover, no significant adverse clinical events have been reported at long-term follow-up and first studies that explored the potential of this technology for the treatment of in-stent restenosis demonstrated safety and efficacy. Although the first clinical experiences with drug-eluting stents have produced stunning results, there are a number of theoretical limitations to these devices, including: 1) limitations of drug loading capacity and 2) ability to control drug elution that could result in unfavorable pharmacokinetics. There are also questions about the durability of the polymer coatings (deformation under mechanical stress, gaps between metal and arterial wall, etc). The thickness of some coatings makes them unsuitable for very small vessels. Finally most biodegradable coatings are prone to chronic inflammation. Since only a polymer-coated bare metal stent remains following the drug's release, the potential for long term polymer biocompatibility problems remains a concern. The potential for some drugs to produce radiation-like effects such as "black holes", malapposed and naked struts and wall thinning are potentially the dark side of this technology and may contribute to late thrombosis, aneurysms or delayed restenosis. Long term clinical follow-up is necessary to assess the long term safety of this technology. There is a legitimate question as to whether drug-eluting stents will produce similar results across all patient subsets encountered in "real-life" interventional practice (e.g. long lesions, small diameter vessels, vein grafts, chronic total occlusions, bifurcated and ostial lesions). Cost-benefit issues also need to be addressed, especially because multivessel stenting and multistent usage is likely to increase.

Twenty-eight-day efficacy and phamacokinetics of the sirolimus-eluting stent.

BACKGROUND: In-stent restenosis is caused by neointimal hyperplasia. Sirolimus (rapamycin; Wyeth Research, Radnor, Pennsylvania, USA) inhibits vascular smooth muscle cell proliferation and we evaluated the efficacy of sirolimus in reducing neointimal formation in a rabbit iliac model and in-vivo pharmacokinetics in the porcine coronary model. DESIGN: Randomized, blinded, prospective animal study. METHODS: Bilateral rabbit iliac artery stent implantation was performed using crossflex stents (Cordis Corporation, Warren, New Jersey, USA) coated with sirolimus incorporated in a nonerodable polymer. Arteries were randomized to one of four stent groups: uncoated stents (n = 8); polymer control stents (n = 10); low-dose sirolimus-eluting stents (n = 9); and high-dose sirolimus-eluting stents (n = 10). Histomorphometry was performed at 28 days. Arterial tissue and stents were retrieved at 8, 14 and 28 days and blood samples were obtained daily during the first week. RESULTS: Treatment with low-dose sirolimus was associated with a 23% (P = NS) reduction in neointimal area and treatment with high-dose sirolimus with a 45% (P < 0.05) reduction. Sustained drug release from the stent and prolonged intramural arterial deposition were confirmed for up to 28 days. No detectable sirolimus was found in the blood after 2 days. CONCLUSION: Controlled-release local delivery of a cell-cycle inhibitor from a nonerodable polymer-coated stent reduced neointimal formation in rabbit iliac arteries in a dose-dependent manner and represents a promising strategy for preventing restenosis.

Morphological and degradation studies of sirolimus-containing poly(lactide-co-glycolide) discs.

The effect of residual solvent and copolymer ratio on the in vitro degradation and drug release behavior of a bioabsorbable polymer/drug system was investigated in an effort to understand and develop the use of these excipients for controlled drug delivery devices. Sirolimus-containing poly(lactide-co-glycolide) (PLGA) discs were fabricated by a solution-casting method using dimethyl sulfoxide (DMSO) as the solvent. The residual DMSO was removed from a set of discs by supercritical carbon dioxide extraction, and reflections of crystalline sirolimus were observed in the wide-angle X-ray scattering profile observed after extraction. A correlation was not observed between the extent of drug crystallization and extraction conditions and copolymer ratio. Mass loss, molecular weight, and sirolimus release were monitored during an in vitro study of the oven-dried neat PLGA, sirolimus-containing PLGA, and extracted sirolimus-containing PLGA discs during 56 days. The sirolimus-containing PLGA discs with residual DMSO exhibited a faster sirolimus release rate compared to the extracted discs. The residual DMSO facilitated release of sirolimus. The discs that contained PLGA with higher glycolide content, particularly 50% glycolide, degraded faster and exhibited faster sirolimus release.

Control of cilostazol release kinetics and direction from a stent using a reservoir-based design.

Sustained release formulations of a potent antithrombotic drug, cilostazol, in poly-(lactic acid-co-glycolic acid) (PLGA) matrices were created for luminal release from a novel drug-eluting stent utilizing reservoirs (RES TECHNOLOGY™). The crystallinity of cilostazol and the morphology of the cilostazol/polymer matrix in the stent reservoirs were examined by cross-polarized optical microscopy and differential scanning calorimetry. An in vitro method was developed to study release kinetics of various cilostazol formulations and to examine correlation with in vivo release. Formulation parameters such as drug-to-polymer ratio and the use of a polymer barrier on the abluminal surface of the drug/polymer matrix were found to be effective in modulating drug release rate. Cilostazol/PLGA(75/25) in the weight ratio of 50/50 to 70/30 displayed first-order release kinetics for the majority of the drug load. Addition of an abluminal polymer barrier slowed cilostazol release rate when compared to the bidirectional reservoir design. Excellent correlation between cilostazol in vivo release profile from stents in a porcine coronary artery model and that measured in vitro in a modified USP-7 apparatus suggests that the in vitro release system is capable of predicting in vivo release of cilostazol from stent reservoirs.

A nonelutable low-molecular weight heparin stent coating for improved thromboresistance.

Low-molecular weight heparin (LMWH) has been widely used as a systemic anticoagulant during percutaneous coronary intervention. In this study, LMWH was covalently immobilized to the surface of a cobalt chromium reservoir-based sirolimus-eluting stent to create a nonelutable nanoscale coating for enhanced thromboresistance. Toludine-blue stained stents revealed uniform heparin coverage on all surfaces of the stent. Scanning electron microscopy of stent strut cross-sections showed identical coating thickness on all sides; while the thickness was determined to be 320 nm by a focus-ion beam system. Secondary ion mass spectrometry showed constant concentrations of O, N, and S atoms throughout the depth of the surface, confirming the uniformity of the heparin coating. The nonelutable nature of the coating was confirmed in a modified Factor Xa inhibition assay which showed the stent had an equivalent of 3-5 heparin units/cm(2), while no elutable heparin was detected in wash solutions. The antithrombin binding capacity of the immobilized heparin was determined to be 60-80 pmol/cm(2) in an antithrombin uptake assay. The enhanced thromboresistance of the heparin coating was demonstrated in an in-vitro bovine blood flow loop which showed minimal visual thrombus accumulation and 95% reduction in platelet deposition compared to uncoated control stents. Drug-eluting stents with such nonelutable LMWH coating would represent a significant advance in the treatment of patients with complex lesions who are at increased risk of developing stent thrombosis.

Microstructure and drug-release studies of sirolimus-containing poly(lactide-co-glycolide) films.

Sirolimus-containing poly(lactide-co-glycolide) (PLGA) films were prepared by solution casting and removing the residual solvent, 1,4-dioxane, by liquid and supercritical carbon dioxide (CO(2) ) extraction. The effect of lactide:glycolide ratio, stereochemistry of PLGA, and extraction condition (i.e., temperature and pressure) on the polymer and drug morphologies was studied using wide-angle X-ray scattering and differential scanning calorimetry. The polymer and drug crystallinity increased after liquid and supercritical CO(2) extraction, and the level of drug crystallinity within the film depended on the extraction conditions. Generally, higher levels of drug crystallinity were observed in the films with amorphous polymer matrices, and the drug crystallinity increased with temperature and pressure of the extraction conditions. In vitro drug elution from these films was studied using a USP 4 apparatus. Polymer crystallinity was found to be the determining factor for drug release, whereby films with higher polymer crystallinity eluted less drug compared to films with amorphous polymer matrices.

Polymers for drug eluting stents.

Currently approved drug eluting stents (DES) consist of a metallic scaffold and an elutable drug dispersed in a polymer matrix that conformally surrounds the struts. These primarily biostable polymers bind the drug to the stent and modulate the elution of the drug into the arterial tissue. This chapter summarizes the key requirements for polymers used in the DES, including physical properties, stability, compatibility with drugs, biocompatibility with vascular tissue and control of drug release. An in-depth analysis of polymer structure, coating design, drug-polymer morphology and drug elution profile is provided for the four currently marketed DES: CYPHER(®) Sirolimus-eluting Coronary Stent, Taxus(®) / Taxus(®) Liberte(®), XIENCE V(™) / Promus(®) and Endeavor Resolute(®). A new generation of DES is being developed using bioabsorbable polymers which degrade over time and leave behind a bare metal stent. This includes the RES TECHNOLOGY™ platform employed in the NEVO™ Sirolimus-eluting Coronary Stent which is explored with respect to polymer composition, degradation profile and drug release kinetics.

Lipoxygenase and prostaglandin G/H synthase cascades in cardiovascular disease.

The 12/15-lipoxygenase (LO) cascade governs the generation of 12-hydroperoxy-eicosatetraenoic acid (HPETE) and 15-HPETE from arachidonic acid. The 5-LO pathway plays a fundamental role in the biosynthesis of leukotrienes, essential inflammatory lipid mediators. Cyclooxygenase (COX)-1 and -2 biosynthetic pathways are responsible for prostaglandin and thromboxane formation. Experimental investigations in animal models using 12/15-LO deficient mice, 12/15-LO or 15-LO transgenic mice, or pharmacological 15-LO inhibition have all demonstrated the essential role of 12/15-LO in atherogenesis. The underlying mechanisms are linked to low-density lipoprotein oxidation, pro-inflammatory Th1 cytokine production and enhanced monocyte-endothelial cell interaction. Human genetic studies as well as disruption of the 5-LO gene in mouse models of hyperlipidemia revealed that 5-LO and 5-LO-activating protein are associated with risks of human cardiovascular disease, and that this cascade plays an important role in aortic aneurysm pathogenesis through leukotriene-mediated inflammatory chemokine production. COX-1 plays an active role in atherogenesis via thromboxane A(2), while COX-2-derived prostaglandin (PGI(2)) protects against atherosclerosis in murine models. Recent data demonstrated that selective inhibition of COX-2 augments the risk of cardiovascular events in patients. Selective inhibition or blockade of selective components in these two enzymatic pathways through systemic drug delivery or medical device approaches (e.g., drug-eluting stents) may have therapeutic benefit against certain cardiovascular diseases.

Sirolimus-eluting stents: a review of experimental and clinical findings.

Sirolimus (rapamycin), a macrolide antibiotic with known potent immunosuppressive properties, acts in the first phase (G1) of the cell cycle, blocking its further progression to the phase of DNA synthesis (S). In experimental models, rapamycin is effective in inhibiting smooth muscle cell proliferation and migration after vessel wall injury with balloon angioplasty. These results lead to the clinical application of sirolimus-eluting stents in 45 patients in Sao Paulo and Rotterdam (FIM Registry) and 238 patients in a randomized, European multicenter trial (RAVEL). These trials showed, by angiography and intravascular ultrasound, almost complete abolition of in-stent late hyperplasia up to one year after the procedure. In this review, we describe the experimental and clinical results of sirolimus-eluting stents including our experience of 26 stents implanted in 17 patients. In elective de novo lesions has shown remarkably clear lumens at follow-up angiography and intravascular ultrasound within the stented segments were observed with no lesion progression at the stent margins or thrombosis after a 2 month regimen of aspirin, and ticlopodine or clopidogrel. New large-scale ongoing clinical trials will investigate the efficacy of sirolimus-eluting stents in lesions that are traditionally associated with high restenosis rates after stent implantation, such as long lesions, bifurcations and instent restenosis.

Differential local effect of sirolimus eluting stent and paclitaxel eluting stent in a porcine restenosis model

Introdução: Os stents farmacológicos liberadores de sirolimus (SES) e de paclitaxel (PES) reduzem de maneira significativa os índices de reestenose se comparados aos stents de metal. Há muita controvérsia com relação aos possíveis efeitos indesejáveis do SES e do PES, como, por exemplo, a trombosesubaguda intra-stent. Este estudo teve como objetivo comparar o efeito arterial local do SES e do PES. Métodos: A dilatação coronariana foi induzida em 16 suínos pela insuflação de um balão superdimensionado na proporção 1.2:1.0 em 43 artérias. Foram olocados aleatoriamente 21 SES e 22 PES na descendente anterior esquerda e na circunflexa esquerda no local da lesão anterior por balão. Os animais foramenviados para necropsia 30 dias após o procedimento. Vinte artérias foram enviadas para análise pelo métodoWestern Blot (16 segmentos com stent + 4 controles normais). Vinte e sete segmentos com stent foram submetidos à análise histológica e à microscopia eletrônica (ME) a baixo vácuo. Resultados: Não foram observadas diferenças com referência às características morfométricas entre os dois grupos. A espessura neointimal se mostrou semelhante nos segmentos com stent SES e PES (0,23±0,05mm vs 0,21±0,08mm, respectivamente – p=0,08). A cicatrização arterial localavaliada pelo método WB demonstrou níveis significantemente mais altos do fator Von Willebrand e CD 31 em SESvs PES (p=0,005 e 0,03, respectivamente). PES demonstrou,ainda, inflamação local mais intensa, expressa pelos níveis mais altos de PDGF (p=0,0007). Este resultado foi corroborado pelos achados de reação inflamatória local mais intensa pela ME, expressa por dados inflamatórios mais elevados no grupo PES. Conclusão: PES demonstrou maior grau de inflamação e menor expressão de CD31 e do fator VonWillebrand, sugerindo, portanto, cicatrização endotelial comprometidaapós a colocação do stent se comparado ao SES.

Background: Sirolimus eluting stents (SES) and Paclitaxel eluting stents (PES) significantly reduce restenosis rates as compared with bare metal stents. There is much controversyregarding possible untoward effects of SES and PES such as subacute stent thrombosis. The present study aimed tocompare the local arterial effect of SES versus PES. Methods: In 16 pigs coronary overstretch was induced by inflating an oversized angioplasty balloon at 1.2:1.0 ratio in 43 arteries. Twenty one SES and 22 PES were randomly deployed in LAD and LCx in the site of previous balloon injury. Animals were sent to necropsy 30 days after the procedure. Twenty arteries were sent to Western Blot (WB) analysis (16 stented segments plus 4 normal controls). Twenty seven stented segments were submitted to histologyanalysis and low vacuum electron microscopy (EM). Results: There were no differences regarding arterial morphometric characteristics between the two groups. Neo intimal thicknesswere similar in SES and PES stented segments (0.23±0.05mm vs 0.21±0.08mm, respectively – p=0.08). Local arterial healing assessed by WB showed significantly higher local levels of Von Willebrand factor and CD 31 in SES vs PES (p values of 0.005 and 0.03, respectively). Also, PES showed higher local inflammation as expressed byhigher PDGF levels (p= 0.0007). This result was corroborated by the EM findings of higher local inflammatory reaction, expressed by higher inflammation scores in the PES group.Conclusion: PES showed higher inflammation and lower expression of CD31 and Von Willebrand factor, suggesting an impaired endothelial healing after stenting when comparedwith SES.